The recent report that rapamycin increases the lifespan of mice is a major breakthrough in aging because it can be translated easily to humans. However, the critical question is whether long-term rapamycin treatment improves healthspan/quality-of-life as well as lifespan. This question must be addressed because of rapamycin's potential negative effects on the immune system. The "GO" grant application presented here is a unique, large, multi-investigator study designed to answer the following questions: (1) Does rapamycin retard/reduce age-related diseases [e.g., cancer, neurodegeneration, atherosclerosis, and nephropathy]? (2) Do mice given rapamycin maintain a better/longer healthspan (e.g., sensitivity of mice to infectious agents, autoimmunity, and biological function)? (3) Does rapamycin improve pathways that impact healthspan (e.g., autophagy and inflammation)? The data generated by this grant will be extremely important to the NIH's mission of improving health because it will provide the first information on how rapamycin-treatment, which increases lifespan, affects the healthspan of mice. The unique "GO" grant mechanism allows us to bring together 21 investigators (with expertise in a variety of areas of aging research) in 9 Projects and 3 Cores to conduct a 2-year comprehensive assessment of rapamycin's effect on the health status of mice. Such a multi-investigator effort is necessary because healthspan is poorly defined and encompasses multiple functions, which potentially interact. It took 2 decades of research funded through "normal" NIH-mechanisms to establish that caloric restriction increased the healthspan of rodents, i.e., the current data show that caloric restriction retards/reduces age-related diseases and improves physiological functions that decline with age. Within 2 years, the data generated by this grant will provide a similar, if not better, assessment of the effect of rapamycin on healthspan. The environment at San Antonio is ideal for conducting such a comprehensive study because of the outstanding animal resources and pathological expertise in the San Antonio Nathan Shock Aging Center, the large number of investigators with expertise in aging (especially using mice to study aging), and our investigators'first-hand experience in feeding rapamycin to mice and measuring rapamycin levels in the diet and blood of mice. We believe that our study meets the goals of the "GO" grants because of the unique nature of the question studied and because the data generated have the potential to immediately stimulate translational research into the effectiveness of rapamycin in treating various age-related diseases in humans. In addition, this application fulfills the goal of the American Recovery and Reinvestment Act of 2009, to provide immediate stimulus to the economy by increasing employment opportunities. For example, funds requested in this application will provide salary support for 23 new positions for technicians/post-doctoral fellows for 2 years and more than 50% of the per diem costs will go for the salaries of new personnel caring for the mice. PUBLIC HEALTH RELEVANCE: The outcomes from this grant will be extremely important to the NIH's mission of improving health because it will provide the first information on the long-term effect of rapamycin on healthspan and the efficacy of using rapamycin to treat a broad range of age-related diseases relevant to humans.